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  • br Conflict of interest statement br Acknowledgements br

    2019-08-29


    Conflict of interest statement
    Acknowledgements
    Introduction Spending their last days on earth having already lost many cognitive functions remains a major fear of elderly people. Although during the last century their lifespans increased, the so-called “old-age diseases” became more and more important. Alzheimer\'s disease (AD) besides cancer, strokes, heart attacks and dementia diseases became the most important diseases of the 21st century; these diseases cause the highest death rates. Nowadays, one person in 200 suffers from any kind of dementia, and this number is expected to double within the next 30 years [1], [2]. Therefore, the scientific and economic interest remains unbroken, and the research for a better understanding of dementia and possible treatments especially of AD have been in progress for decades. The large number of patients suffering from AD makes this disease of special interest within the field of dementia diseases. Many theories regarding the causes of these diseases were postulated, resulting in some therapeutic concepts. One of the most often followed ideas is the β-amyloid hypothesis basing essentially on the neurotoxic effect of β-amyloid plaques inside the human brain having been formed by the action of α-, β- and γ-secretases [3], [4]. However, about 30 percent of middle-aged people have AD-equal amounts of these plaques but without suffering from AD [5], [6]. In addition, several therapies basing on this theory failed to increase the cognitive abilities [7], [8], [9], [10] by decreasing the β-amyloid plaque\'s concentration. Other therapeutic targets refer, for example, to inflammatory processes or mitochondrial disorder of the τ-protein [11], [12], [13]. Another concept relies on the neurotransmitter Bleomycin A5 hydrochloride kinase (ACh) since its concentration seems reduced during AD; AD typical symptoms such as amnesia or behavioral disorders [14], [15], [16], [17] have been credited to a lowered concentration of ACh. Usually, the cleavage of this neurotransmitter is performed by the hydrolase acetylcholinesterase (AChE, E.C. 3.1.1.7) but another enzyme, butyrylcholinesterase (BChE, E.C. 3.1.1.8), seems also important for controlling the concentration of ACh in different tissues of an organism including the brain. It was assumed that BChE is able to compensate a lack of AChE activity [18], [19]. Furthermore, the AChE/BChE ratio in the brain alters from 0.2 in healthy brains to 11 during advanced AD [14], [20], [21]. Thus, both enzymes represent interesting targets for potential AD cures or – at least - as tools for a deeper insight into AD\'s pathology. Triterpenes represent a group of pharmacologically active substances having already been tested for cholinergic activities [22], [23], [24]. Triterpenes holding hopyl [25], lanostyl [26] or lupyl [27] skeletons have been targets in recent studies. Also, pentacyclic triterpenoic acids and compounds derived thereof showed an inhibitory potential for AChE in micromolar range [28]. Especially several subgroups of α- and β-amyrins were most effective inhibitors for this cholinesterase. Furthermore, AChE inhibition has been found for derivatives of oleanolic acid [29], [30], [31], [32], ursolic acid [33] as well as of glycyrrhetinic acid [34] or platanic acid derived compounds [35]. Therefore, we decided to synthesize and to test several ursolic and oleanolic acid (Fig. 1) derived compounds in Ellman’s assays for their ability to act as inhibitors of AChE as well as of BChE and to obtain inhibitory constants (Ki and Ki′).
    Results and discussion
    Conclusions
    Experimental
    Modelling
    Acknowledgements The authors like to thank Dr. Ralph Kluge for ESI-MS and Dr. Dieter Ströhl and his team for the NMR measurements. The IR and optical rotations were measured by Mrs. U. Lammel, MSc. J. Wiese and B.Sc. V. Simon. We like to thank Dr. St. Schwarz for his help in the screening. Support by the “ScienceCampus Halle WCH (W13004216 to RC)” is gratefully recognized.